Bradley R. Cairns
Professor and Chair of Oncological Sciences and Adjunct Professor of Biochemistry
Chromatin Transcription, Genomics, Gene Expression
We are interested in how epigenetics, transcriptional regulation and chromosome dynamics regulate cell growth, development, aging, and cancer. Questions addressed in our lab include: What is the state of the genome and chromosomes at the 'start' of embryonic development - how is the genome packaged and poised in germ cells (sperm and egg) to prepare for embryo development - how do chromatin changes guide gene expression and embryo development - and how is chromatin misregulated in cancer and aging? We are also very interested in the machines that remodel chromosomes to help package or expose genes – to silence or activate those genes properly. We approach these and other biological problems with a variety of techniques including biochemistry, genetics, and genomics. We address these biological problems in yeast, zebrafish, mice and human cells.
Chromatin is remarkably dynamic, as structures formed to silence transcription are remodeled and modified to enable transcription in response to cell signals. The primary unit of chromatin structure is the nucleosome, which wraps genomic DNA like beads on a string. Chromatin transitions are mediated by protein complexes that either reposition nucleosomes, covalently modify nucleosomes, or methylate the DNA – and there is coordination among them. For example, Remodeler complexes use ATP hydrolysis to reposition nucleosomes on the DNA, thereby revealing the underlying sequence to transcriptional regulators. Also, DNA methylation leads to a heritable form of gene silencing, but is regulated by histone modification patterns. We aim to understand these relationships and the enzyme complexes that conduct these processes in normal cells, and their misregulation in cancer and aging.
Remodeler Mechanism and Regulation
Our lab has made fundamental contributions to understanding Chromatin Remodeling Machines. We established that Remodelers use ATP-dependent DNA translocation to pump DNA around nucleosomes to conduct nucleosome sliding and ejection to expose DNA to transcription factors, and we have revealed many domains and proteins that regulate Remodelers (Clapier et al., Molecular Cell, 2017) – and have connected their misregulation to cancer. This team includes Cedric Clapier, Margaret Kasten, Tim Mulvihill, Mary Nelson, Alisha Schlichter and Naveen Verma.
Defining ‘On’ and ‘Off’ Genes in the Early Vertebrate Embryo
We use zebrafish to understand the logic of how chromatin packaging helps control genes that regulate development and pluripotency. Remarkably, we found that housekeeping genes and developmental genes are packaged very differently in early embryos – both genes have special nucleosomes, but developmental genes are reprogrammed to have special silencing structures (Potok et al., Cell 2013; Murphy et al., Cell 2018). Here, Graham Hickey, Yixuan Guo and Candice Wike are exploring the transcription and chromatin factors and structures sculpt the chromatin landscape of early embryos to determine how housekeeping genes are selected to turn on, and which developmental genes are on or off at the onset of zygotic transcription. Here, we have recently uncovered an ordered pathway of transcription factors, histone variants, and histone modification complexes that ‘poise’ developmental genes for future activation, or alternatively activate housekeeping genes - and how they work to reprogram the maternal genome. Our work in zebrafish embryos complements our work on mammalian embryos, below.
Chromatin Programming in Germ Cells and Embryos to create ‘Totipotency’
We provided the first evidence that genes for embryo development are poised by chromatin in the sperm cell (Hammoud et al., Nature 2009), suggesting the inheritance of gene regulatory information. We have extended this to understand the chromatin and transcription pathways that are present in spermatogonial stem cells (SSCs), to better understand ‘totipotency’ – the ability to become any cell type. Here, we are exploring both the mammalian germline and early embryos. To understand male germline stem cells, Jingtao Guo, Chongil Yi and Xichen Nie have established a transcriptional and chromatin ‘cell atlas’ of the human testis using single-cell approaches, which have recently extended to provide atlases of puberty and transfemales – and will next study aging. Regarding our work in mammalian embryos, work by Pete Hendrickson discovered a major driver of embryo transcription and chromatin structure in mammals, termed DUX (Nature Genetics, 2016). Remarkably, DUX expression in embryonic stem cells can covert them to cells that are truly totipotent, which can create both embryonic and extra-embryonic tissues. Here, Edward Grow, Christy Smith, Brad Weaver and Sean Shadle and are greatly extending this work to understand how DUX factors are regulated, how they regulate developmental potential, and how they are misregulated in cancer and disease.
Guo J, Nie X, Giebler M, Mlcochova H, Wang Y, Grow EJ; DonorConnect, Kim R, Tharmalingam M, Matilionyte G, Lindskog C, Carrell DT, Mitchell RT, Goriely A, Hotaling JM, Cairns BR. (2020) The Dynamic Transcriptional Cell Atlas of Testis Development during Human Puberty. Cell Stem Cell.
Murphy PJ, Wu SF, James CR, Wike CL, Cairns BR. (2018) Placeholder Nucleosomes Underlie Germline-to-Embryo DNA Methylation Reprogramming. Cell 172(5):993-1006
Guo J, Grow EJ, Yi C, Mlcochova H, Maher GJ, Lindskog C, Murphy PJ, Wike CL, Carrell DT, Goriely A, Hotaling JM, Cairns BR. (2017) Chromatin and Single-Cell RNA-Seq Profiling Reveal Dynamic Signaling and Metabolic Transitions during Human Spermatogonial Stem Cell Development. Cell Stem Cell 21(4):533-546
Hendrickson PG, Doráis JA, Grow EJ, Whiddon JL, Lim JW, Wike CL, Weaver BD, Pflueger C, Emery BR, Wilcox AL, Nix DA, Peterson CM, Tapscott SJ, Carrell DT, Cairns BR. (2017) Conserved roles of mouse DUX and human DUX4 in activating cleavage-stage genes and MERVL/HERVL retrotransposons. Nat Genet 49(6):925-934
Clapier CR, Kasten MM, Parnell TJ, Viswanathan R, Szerlong H, Sirinakis G, Zhang Y, Cairns BR. (2016) Regulation of DNA Translocation Efficiency within the Chromatin Remodeler RSC/Sth1 Potentiates Nucleosome Sliding and Ejection. Molecular Cell 62(3):453-61
Parnell TJ, Schlichter A, Wilson BG, Cairns BR. (2015) The chromatin remodelers RSC and ISW1 display functional and chromatin-based promoter antagonism. Elife 4:e06073
Hammoud SS, Low DH, Yi C, Carrell DT, Guccione E, Cairns BR. (2014) Chromatin and transcription transitions of mammalian adult germline stem cells and spermatogenesis. Cell Stem Cell 15(2):239-53
Potok ME, Nix DA, Parnell TJ, Cairns BR. (2013) Reprogramming the maternal zebrafish genome after fertilization to match the paternal methylation pattern. Cell 153(4):759-72
Khoddami V, Cairns BR. (2013) Identification of direct targets and modified bases of RNA cytosine methyltransferases. Nature Biotechnology 31(5):458-64
Clapier C and Cairns BR. (2012) Regulation of ISWI involves inhibitory modules antagonized by nucleosomal epitopes. Nature 492(7428):280-4
Wu SF, Zhang H, Cairns BR. (2011) Genes for embryo development are packaged in blocks of multivalent chromatin in zebrafish sperm. Genome Res 21(4):578-89
Hammoud S, Nix D, Haiving Z, Purwar J, Carrell D, Cairns BR. (2009) Distinctive Human Sperm Chromatin Packages Genes Guiding Embryo Development. Nature 460(7254):473-8